This invention relates to a method for the treatment of preeclampsia and of preterm labor with calcitonin gene-related peptide (CGRP) or CGRP/CGRP receptor-based analogue and combinations with a progestational agent (with or without a nitric oxide synthase substrate such as L-arginine, a nitric oxide donor or both), alone or in further combination with one or more of a cyclooxygenase inhibitor, a PGI.sub.2 -mimetic, a thromboxane (TXA.sub.2) inhibitor, A compound possessing TXA.sub.2 -agonistic and TXA.sub.2 -inhibiting properties, a compound possessing TXA.sub.2 antagonistic and PGI.sub.2 -mimetic activities, and a TXA.sub.2 antagonist, and to pharmaceutical compositions comprising such a combination.
Preeclampsia, toxemia, or eclampsia of pregnancy can be significant health problems during pregnancy and are the leading causes of fetal growth retardation, fetal mortality, premature birth, and maternal mortality. The etiology of this pathology is largely unknown and effective therapy is not available. Preeclampsia of pregnancy is characterized by a triad of hypertension, pathological edema and proteinuria. This disease affects 6 to 10% of all pregnancies.
Nitric oxide (NO) has been shown to be the endothelium derived relaxing factor (EDRF) generated from the endothelium of blood vessels. Nitric oxide is a major mediator in the control of vascular relaxation. Nitric oxide is synthesized from L-arginine by nitric oxide synthase located in endothelial and other cells. Nitric oxide can also be generated by application of various nitric oxide donors such as sodium nitroprusside, nitroglycerin, SIN-1, isosorbid mononitrate, isosorbid dinitrate, and the like.
Treatment of pregnant rats with nitric oxide synthase inhibitors, e.g., analogues of L-arginine such as N.sup.G -nitro-L-arginine methyl ester (L-NAME), results in elevated blood pressure, fetal growth retardation and proteinuria. Thus, inhibition of nitric oxide synthesis produces conditions and symptoms identical to preeclampsia of pregnancy and indicates that preeclampsia is the direct result of the decrease in nitric oxide synthesis and/or a change in the regulation of vascular tone. These condition give rise to increased blood pressure, decreased blood flow to the fetus, retarded fetal development, and proteinuria. Agents that raise nitric oxide levels therefore are useful in the treatment of preeclampsia of pregnancy. Nitric oxide donors also reduce uterine contractility during pregnancy and are useful for treating preterm labor. The nitric oxide effects of CGRP on blood pressure (BP) may be dependent upon the activation of guanylate cyclase and generation of cGMP to produce relaxation.